The enzyme steroid C17,20 lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17xcex2-carbon position to form important precursor molecules to the formation of testosterone, 5xcex1-dihydrotestosterone and the estrogens, principally estrone and estradiol. Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders. A treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production. Moreover, such an enzymatic treatment is a much more focused treatment in that it is directed to the immediate hormonal imbalance believed responsible for the condition, as opposed to a broad spectrum remedy which not only affects the particular symptom, but causes permanent endocrine defects necessitating life-long dependency on replacement therapy.
It is further known that certain types of breast cancers are estrogen dependent. Adrenalectomy, ovariectomy and hypophysectomy have been employed as well as non-surgical techniques resulting in tumor regressions. It has been shown that human patients with advanced breast cancer, who are administered estrogen biosynthesis enzyme inhibitors, show dramatically reduced plasma estradiol levels and improved therapeutic effects, at least as effective as adrenalectomy. (Jean Van Wauve and Paul A. J. Janssen, Journal of Medicinal Chemistry, 32, 10:2231-2239).
Prostatic cancer, or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% for all patients tested. (Cookson C. S. and Sarosdy, M. F., South Med. J 87:1-6).
More specifically, C17,20 lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinoma, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated C17,21 lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas.
The enzyme steroid 5xcex1-reductase, present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17xcex2-hydroxy-androstan-4-en-3-one) into dihydrotestosterone or DHT (17xcex2-hydroxy-5xcex1-androst-3-one), which is also known as stanolone. DHT is a more potent androgen than testosterone, and acts as an end-organ effecter in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5xcex1-reductase. In the treatment of androgen dependent disorders, such as benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable.
The conversion of testosterone to DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts. For example, high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris.
Agents which have the ability to inhibit both C17-20 lyase and 5xcex1-reductase would not only inhibit DHT production, but also testosterone formation. In inhibiting the principal androgenic steroidal hormones, such compounds would have enhanced utility in the treatment of androgen disorders.
The enzyme C17-hydroxylase catalyzes the C17 hydration of steroid substrates during the biosynthesis of cortisol. As C17-20 lyase and C17-hydroxylase are different active sites of the same enzyme, the inhibition of one usually results in the disabling of the other. Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing""s syndrome and hypertensive conditions. Inhibition of cortisol synthesis via C17xcex1-hydroxylase would therefor have therapeutic effect for the treatment of these disorders or conditions.
The present invention relates to 4-aza-17-(cyclopropoxy)-androst-5xcex1-androstan-3-one, 4-aza-17-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of C17-20 lyase and/or 5xcex1-reductase, including androgen and estrogen ediated disorders, such as, for example benign prostatic hyperplasia, DHT-mediated disorders, such as, for example, acne, estrogen dependent breast cancer and androgen mediated prostatic cancer. As the present compounds also disable the operation of C17xcex1-hydroxylase, disorders which are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention. For example, hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing""s syndrome and hypertensive conditions.
In another embodiment, the compounds of the invention may be administered in combination with other effective treatment for enhanced therapeutic effect. For example, in the treatment of androgen-dependent disorders, including prostatic cancer, flutamide, a known androgen receptor antagonist may be used in combination with the compounds of the invention.
More particularly, the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, having the following general formula: 
wherein:
A is O or NH;
R1 is H or C1-4 alkyl;
R2 is halo, phenylthio, phenylsulfinyl or phenylsulfonyl;
R3 is halo, C1-4 alkylthio, C1-4 alkylsulfinyl or C1-4 alkylsulfonyl;
R4 is H, C1-4 alkyl or C2-4 alkenyl;
R5 is H, C1-4 alkyl;
Z can be:
a) oxo;
b) (H)(H) or an a-hydrogen and a xcex2-substituent selected from the group consisting of: C1-4 alkyl, C2-4 alkenyl, hydroxy, C1-4 alkanoyloxy, C1-4 alkoxycarbonylmethyl, carboxymethyl, C1-4 alkoxycarbonyl, carboxy, C1-4 alkanoyl and halo;
xe2x80x83with the proviso that when:
a) R2 is present and is other than hydrogen, a 1,2-double bond is present, and
b) Z is oxo a 6,7, double bond is not present.